The Redesign of the Molecular Scaffold of Viral Ion Channel Blockers

Zsidó, Balázs Zoltán and Mernyák, Erzsébet and Kopasz, Zoltán and Földes, Fanni and Leiner, Krisztina and Madai, Mónika and Zana, Brigitta and Kuczmog, Anett and Hetényi, Csaba (2026) The Redesign of the Molecular Scaffold of Viral Ion Channel Blockers. COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL, 35 (1). ISSN 2001-0370

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Abstract

The rise of rapidly mutating viruses poses growing challenges for drug developers in the fight against antiviral resistance. Viral ion channels generally have low mutation rates and are therefore considered emerging targets for a sustainable solution to the problem of resistance. This study reports the redesign of scaffolds for drug candidates targeting viral ion channels. The redesign was powered by a combination of a computational docking protocol that accounts for water molecules (HydroDock) and a subsequent quantum mechanics-based scoring (QMH-L) of the drug candidates. Extending the antiviral amantadine led to new compounds that better match the alternating hydrophobic and hydrophilic patterns of the inner walls of ion channels—a common feature across many viruses. Simplifying the structure yielded a cyclohexylamine-based minimalist scaffold that demonstrates improved antiviral activity compared to other agents such as amantadine and arterolane. SARS-CoV-2 variants served as test systems in laboratory experiments. The new molecular scaffolds presented here provide a strong foundation for designing potent viral ion channel blockers, helping to fill the drug pipeline.

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